Department of Microbiology and Immunology, Indiana University School of Medicine-Northwest, Gary, Indiana, 46408, USA.
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Suwon, 16419, Korea.
Sci Rep. 2018 Feb 6;8(1):2521. doi: 10.1038/s41598-018-20617-5.
In Staphylococcus aureus, an important Gram-positive human pathogen, the SaeRS two-component system is essential for the virulence and a good target for the development of anti-virulence drugs. In this study, we screened 12,200 small molecules for Sae inhibitors and identified two anti-cancer drugs, streptozotocin (STZ) and floxuridine (FU), as lead candidates for anti-virulence drug development against staphylococcal infections. As compared with STZ, FU was more efficient in repressing Sae-regulated promoters and protecting human neutrophils from S. aureus-mediated killing. FU inhibited S. aureus growth effectively whereas STZ did not. Intriguingly, RNA-seq analysis suggests that both compounds inhibit other virulence-regulatory systems such as Agr, ArlRS, and SarA more efficiently than they inhibit the Sae system. Both compounds induced prophages from S. aureus, indicating that they cause DNA damages. Surprisingly, a single administration of the drugs was sufficient to protect mice from staphylococcal intraperitoneal infection. Both compounds showed in vivo efficacy in a murine model of blood infection too. Finally, at the experimental dosage, neither compound showed any noticeable side effects on blood glucose level or blood cell counts. Based on these results, we concluded that STZ and FU are promising candidates for anti-virulence drug development against S. aureus infection.
在金黄色葡萄球菌（一种重要的革兰氏阳性人类病原体）中，SaeRS 双组分系统对于其毒力至关重要，也是开发抗毒力药物的理想靶点。在本研究中，我们筛选了 12200 种小分子以寻找 Sae 抑制剂，并发现两种抗癌药物链脲佐菌素（STZ）和氟尿嘧啶（FU）是针对金黄色葡萄球菌感染开发抗毒力药物的潜在候选药物。与 STZ 相比，FU 更有效地抑制 Sae 调控的启动子，并保护人中性粒细胞免受金黄色葡萄球菌介导的杀伤。FU 能有效抑制金黄色葡萄球菌的生长，而 STZ 则没有。有趣的是，RNA-seq 分析表明，这两种化合物比抑制 Sae 系统更有效地抑制其他毒力调控系统，如 Agr、ArlRS 和 SarA。这两种化合物均能诱导金黄色葡萄球菌的噬菌体，表明它们会引起 DNA 损伤。令人惊讶的是，单次给药即可保护小鼠免受金黄色葡萄球菌腹腔感染。这两种化合物在血源性感染的小鼠模型中也表现出体内疗效。最后，在实验剂量下，这两种化合物对血糖水平或血细胞计数均无明显副作用。基于这些结果，我们得出结论，STZ 和 FU 是开发针对金黄色葡萄球菌感染的抗毒力药物的有前途的候选药物。
